PB2335: TRIAL IN PROGRESS: PHASE 3 TRIAL EVALUATING THE EFFICACY AND SAFETY OF ODRONEXTAMAB PLUS CHOP (O-CHOP) VERSUS R-CHOP IN PREVIOUSLY UNTREATED DIFFUSE LARGE B-CELL LYMPHOMA (OLYMPIA-3)
Authors: Benoit Tessoulin, Stephanie Guidez, Manjusha Namuduri, Ashish Risal3, Alpana Waldron, Nickolas A. Sophos, Amulya Uppala, Min Zhu, Siobhán Nolan, Jurriaan Brouwer-Visser, Aafia Chaudhry, Srikanth Ambati, Hesham Mohamed, David Tucker
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: While the first-line combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has improved outcomes for diffuse large B-cell lymphoma (DLBCL), up to 40% of patients will experience relapsed/refractory (R/R) disease (Sehn & Salles. NEJM, 2021). There is an unmet need to improve and deepen responses to first-line therapy, especially in patients with high-risk features where outcomes are particularly poor. Odronextamab is an off-the-shelf CD20xCD3 bispecific antibody that triggers T-cell-mediated toxicity of malignant B cells. In the Phase 2 ELM-2 study (NCT03888105), odronextamab monotherapy demonstrated clinically important antitumor activity (objective response rate, 49%; complete response [CR] rate, 31%) and a generally manageable safety profile with the optimized step-up regimen (0.7/4/20 mg) in patients with heavily pre-treated, R/R DLBCL (Kim, et al. ASH, 2022). Given these promising results and the current unmet medical need, it is warranted to explore if combining odronextamab with CHOP (O-CHOP) as first-line treatment can improve outcomes of patients with International Prognostic Index (IPI) intermediate- to high-risk DLBCL. Aims: The OLYMPIA-3 trial aims to compare the efficacy and safety of O-CHOP with R-CHOP in patients with previously untreated DLBCL that have IPI intermediate- to high-risk features. Methods: OLYMPIA-3 is a Phase 3, open-label, randomized, multicenter study that will involve approximately 200 sites globally to enroll a maximum of 48 patients in Part 1 (safety run-in) and approximately 840 patients in Part 2 (randomization). Part 1 of this trial will establish the safety and tolerability of combining odronextamab with CHOP. In Part 2, patients with IPI ≥2 will be randomized 1:1 to compare the efficacy of O-CHOP versus R-CHOP (Figure). CHOP will be administered on Day 1 for 6×21-day cycles. Odronextamab will be given intravenously with a step-up dosing schedule during Cycle 1 and Cycle 2 to mitigate the risk of cytokine release syndrome (CRS). Odronextamab is introduced 1 week after CHOP to allow for debulking and potentially to further mitigate the risk of CRS. R-CHOP will be administered per standard of care for 6 cycles. Eligible patients are aged ≥18 years with previously untreated CD20-positive DLBCL, measurable disease, IPI ≥2, Eastern Cooperative Oncology Group performance status ≤2, and adequate organ function. For Part 1 only, patients are required to have ≥1 high-risk feature such as IPI 3–5, non-germinal center B-cell type cell of origin, or double/triple-hit lymphoma (Sehn & Salles. NEJM, 2021). Exclusion criteria include primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS non-Hodgkin lymphoma, significant CNS pathology, peripheral neuropathy Grade ≥3, and evidence of any active infection. All patients will provide informed consent. Results: The primary endpoint is progression-free survival by independent central review (ICR), with key secondary endpoints of event-free survival and CR by ICR, as well as overall survival. Summary/Conclusion: OLYMPIA-3 will determine the tolerability and clinical efficacy of O-CHOP versus R-CHOP as first-line treatment in patients that have IPI intermediate- to high-risk DLBCL.Keywords: Monoclonal antibody, Diffuse large B cell lymphoma, Bispecific, Non-Hodgkin's lymphoma